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Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

Abstract : Tumors defective for DNA polymerase (Pol) e proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol e proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol e proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol e proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol e mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol e.
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Karl Hodel, Richard de Borja, Erin Henninger, Brittany Campbell, Nathan Ungerleider, et al.. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair. eLife, eLife Sciences Publication, 2018, 7, pp.e32692. ⟨10.7554/eLife.32692⟩. ⟨hal-01737948⟩

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